Essential tremor (ET) is among the most common neurological diseases, with a prevalence (age >40 years) estimated to be 4.0% and prevalence in advanced age (>90 years) exceeding 20.0%. The underlying pathogenesis remains poorly understood and, as a consequence, current medications are empiric and of limited efficacy. There are only two front-line medications, a situation that has not changed in more than 30 years, and one in two patients simply stops these medications due to poor efficacy. The foremost obstacle to the study of pathogenesis is the absence of an animal (genetic) model for this disease. ET (often referred to as "familial tremor"), is generally regarded as a highly-genetic disorder, with physicians commonly seeing families with affecteds over multiple generations, and twin studies showing high concordance among monozygotes. Despite this, as of 2010, genetic studies have not advanced to the point where susceptibility genes have been identified. Previously published studies of linkage in families suggest that susceptibility loci contribute to the etiology of ET. In the current application we will build on previous studies and propose to use a linkage and resequencing approach to identify susceptibility genes for familial early-onset (<40 years) ET. To overcome the problems associated with previously published genetic studies of ET, which did not use strict phenotype definition in assigning affectedness status, we will use strict diagnostic criteria of 'definite'or 'probable'ET for inclusion of probands and affected individuals in families and further restrict our inclusion to individuals with pure ET (i.e. no dystonia) to reduce heterogeneity and to increase our power to detect a linkage signal. We will also focus on multiplex and multigenerational early onset ET families. To date we have already identified 96 families with an affected proband and >2 living first-degree relatives with ET and in 74 (77%) of families, the proband's age at onset was <40 years. PUBLIC HEALTH RELEVANCE: ET, a highly genetic disorder, is the most common cause of tremor in humans, affecting large numbers of individuals worldwide. Current treatments, which are largely unsuccessful, are empiric. Therapies based on an understanding of disease pathogenesis are needed, yet the absence of any identified genes and the resultant lack of an animal model, is the foremost obstacle standing in the way of these studies.